Methamphetamine (MA) dependence is a highly disabling and refractory condition, which results in serious impairment in social and occupational functioning. Although the endemic of MA use appears to have stabilized, MA is still the second most widely used illicit drug in the world, and the public health problem associated with MA use continues to increase. However, no medication to date has been approved by the FDA for the treatment of MA dependence in the United States and the clinical need for more effective pharmacotherapies remains significant. We therefore propose citicoline (CDP-choline as a nutritional supplement) for the potential adjunctive treatment of MA dependence as a response to RFA-DA-09-005, "Pilot Clinical Trials of Pharmacotherapies for Substance Related Disorders". Citicoline has demonstrated efficacy in treating a number of central nervous system disorders. The mechanism includes activation of the biosynthesis of structural phospholipids in neuronal membranes and an increase of norepinephrine and dopamine levels in the central nervous system. We have utilized a multi-modal neuroimaging approach for the investigation of MA dependence. Most recently, we have found that citicoline tends to decrease MA use and, importantly, to increase frontal lobe N-acetylaspartate (NAA, a marker of neuronal viability or integrity) levels in MA dependent subjects, which suggests recovery of neuronal viability and cognitive function. Chronic MA subjects have cognitive deficits, including impaired executive function, episodic memory and information processing speed, and verbal memory/fluency and inhibitory function. The cognitive deficits are closely related to both relapse to MA use and ineffective psychosocial treatment outcomes. Citicoline may attenuate desire for MA use and improve cognitive performance, making treatment more effective in motivated subjects. The goal of the proposed study is to systematically evaluate the therapeutic effects of citicoline in 74 MA dependent young adults. An eight week, randomized, prospective, double-blind, placebo-controlled, parallel group design, clinical trial will be conducted. Age, sex matched 37 healthy subjects also will be enrolled for baseline and follow-up comparison to MA dependent subjects. We plan to receive participant referrals from Assessment and Referral Services (ARS), which provides assessments for several thousand Salt Lake County residents with substance abuse disorders and no health insurance each year. In this application, we will take advantage of both neuropsychological measures and multimodal neuroimaging techniques such as magnetic resonance spectroscopy, diffusion tensor imaging and brain cortical thickness measure to investigate the efficacy of citicoline in reducing drug use and improving brain function. We believe neuroimaging is an essential tool for the parallel examination since it provides important information on treatment-related change in cerebral structure and function in vivo. PUBLIC HEALTH RELEVANCE: This application will evaluate citicoline as an adjunctive treatment in MA dependent subjects who are awaiting treatment. The complementary measures of both neuropsychological function and multimodal neuroimaging following an 8-week citicoline trial will provide new insights and treatment strategies for this significant public health concern.